This project focuses on the preclinical development of a novel, and efficient non-invasive therapeutic strategy to test the delivery of low-dose of carbon monoxide (CO) using a CO-releasing molecule 401 (CORM401) for the treatment of TBI etiopathology commonly observed in young active adults and also in the elderly. Contrary to the traditional view of CO as a toxic agent, we were among the pioneer to show that CO can be neuroprotective at low doses. Knowing from our previous studies that exposure to CO beginning immediately after a brain insult is protective in transient and also in permanent focal cerebral ischemia models, we now plan to investigate whether CORM401 has similar remarkable neuroprotective effect. Here, we will determine the optimal doses and therapeutic window for CORM401 treatment, along with its inactive control (iCORM401). We combine effort with our collaborator who has been a pioneer in the development and test of CORMs. We now propose to test CORM401 since it would not have the toxicity associated with the other CORMs based on their transition metals and also because if can release up to three molecule of CO as compared to only one. We hypothesize that CORM401 would have therapeutic effect to decrease lesion size, hippocampal edema, and behavioral deficits in the controlled-cortical impact TBI model, and whether this beneficial effect would be at least partially due to the Nrf2 contribution, known as a master cytoprotective pathway leading to the upregulation of various protective proteins, which would result to a ?positive feed-forward mechanism? for neuroprotection. Thus, the Aim 1 is to determine whether CORM401 post-treatment is sufficient to reduce anatomical and functional deficits after TBI and whether the beneficial outcomes would be sustained in older (18-20mo) animals as compared to younger ones (3-3.5mo). The Aim 2 is to investigate the beneficial CORM401 mechanism of action and determine whether Nrf2 pathway is at least partially responsible for such neuroprotection. Various anatomical, functional, and brain imaging outcomes will be investigated blindly after such acute brain trauma. The novelty of our study resides notably in our unique team experience in this field and in the potential therapeutic use of CO, recognizing that that both physicians and regulatory bodies remain rather skeptical, we have now focused on testing the ?improved? CO-releasing molecule, i.e. CORM401. We also selected the CORM401 vs its inactive control to rigorously test our hypothesis and to further monitor potential side effects since it does not have the toxicity associated with other CORMs and also because it can release more CO. Such an intriguing hypothesis is timely, innovative and needs to be tested first in such proposed preclinical model to move forward, and it holds the potential to unmask therapeutic strategies and new mechanisms against young and older male and female adult brain trauma.